The shortage of human organ donors is a critical limitation in the widespread use of transplantation as a treatment for serious diseases. The use of non-human species, particularly the pig, as organ donors offers a potential solution to this shortage of donor organs. The use of tissues from other species (xenografts) has largely been unsuccessful because of a lack of understanding of the nature of the host's immune response to xenografts and the failure of current immunosuppressive techniques to allow for long-term graft survival. The early phases of the xenograft rejection reaction are dominated by humoral immune responses and the experiments proposed in this application are designed to establish a more complete understanding of this component of the host response. We intend identify the immunoglobulin genes that control the antibody response(s) mounted by patients exposed to pig tissues, isolate and characterize human antibodies that have the functional capacity to mediate rejection of pig xenografts, and identify the specific subsets of B lymphocytes that produce these antibodies. Our previous experimental work in rodents has demonstrated the xenograft response appears to be a unique form of T cell-independent antibody production controlled by a closely-related group of Ig genes. We have proposed that this type of immune response is a common feature of the early xenograft reaction, even for diverse species combinations, and the experiments outlined in this proposal are intended to extend these studies to an examination of the human antibody response to pig xenografts. We believe if a small group of closely-related immunoglobulin genes are responsible for controlling the humoral response of xenografts in patients, this information may provide the basis for the development of new strategies for preventing this reaction.